Oxidative stress has been known to contribute to a variety of human degenerative diseases associated with aging, such as Parkinson's disease and Alzheimer's disease, as well as to Huntington's Chorea, diabetes and Friedreich's Ataxia (Allen, S., et al., J. Biol. Chem. 278:6371-6383, 2003; Hirai, K., et al., J. Neurosci. 21:3017-3023, 2001) and to non-specific cellular damage that accumulates with aging.
Mitochondria are the intracellular organelles primarily responsible for energy metabolism, and are also the major source of the free radicals and reactive oxygen species (“ROS”, such as hydrogen peroxide and the superoxide radical anion (O2−.)) that cause oxidative stress and/or damage inside most cells (Murphy M P, Smith R A., Ann. Rev Pharmacol Toxicol. 2006 Oct. 2; Epub ahead of print). Mitochondria are equipped to detoxify hydrogen peroxide due to the presence of antioxidant enzymes (peroxiredoxins, thioredoxins, and GSH-dependent peroxidases (Chang, T. S., J. Biol. Chem. 279, 41975-41984, 2004). Typically, mitochondrial superoxide (O2{dot over (−)}., the radical anion produced by one electron reduction of O2) is dismutated according to the stoichiometry shown below, by manganese superoxide dismutase (MnSOD) that is localized within the mitochondrial matrix.2O2 .+2H+→O2+H2O2 
However, when cellular ROS production exceeds the cell's detoxification capacity, oxidative damage can occur. This damage disrupts mitochondrial function and oxidative phosphorylation and leads to significant cellular damage to mitochondrial, cytoplasmic or nuclear cellular proteins, DNA, RNA and phospholipids and thus induces cell damage, death and/or disease. Superoxide can also react with nitric oxide at a diffusion-controlled reaction rate, forming a highly potent oxidant and peroxynitrite that can modify proteins and DNA through oxidation and nitration reactions (Beckman, J. S., et al., Nature 364, 584, 1993). In addition to these damaging and pathological roles, ROS also act as a redox signaling molecule(s) and promotes cell proliferation, DNA damage repair errors and mutation leading to inflammatory hyper-proliferation, neoplasia and malignancy (see Michikawa et. al., “Aging-dependent large accumulation of point mutations in the human mtDNA control region for replication.” Science. 1999 Oct. 22; 286(5440):774-9).
Naturally occurring exogenous and endogenous tissue reactive oxygen species (ROS) are known to play a major role in prostate, colorectal, lymphoma and pancreatic carcinogenesis (De Marzo et al, J Cell Biochem. 2004 Feb. 15; 91(3):459-77; Reliene R, Schiestl R H. Antioxidants suppress lymphoma and increase longevity in ATM-deficient mice. J Nutr. 2007 January; 137(1):229S-32S). ROS alters the activity of thiol-dependent enzymes, changes the cellular redox balance and covalently modifies proteins and modifies and mutagenizes DNA (Sikka S C., Curr Med Chem. 2001 June; 8(7):851-62. Kamat A M, Lamm D L. W V Med J. 2000; 96: 449-54). It has also been shown that increased lipid peroxidation and production of high levels of unregulated ROS in men with high fat diets is one of the major reasons for the higher incidence of prostate cancer in industrialized nations, as compared to that in developing countries (Dargel, R., Exp Toxic Pathol 1992, 44:169-181). In recent years, direct experimental evidence has linked increased ROS levels with the corresponding increase in mutations and tumor development in various tissues, including in the pancreas and the prostate organs (Oberley et. al., The Prostate, 2000: 44: 144-155). For example, Oberley and his colleagues monitored oxidative stress induced enzymes and oxidative damage to DNA bases of malignant and normal human prostate tissues. Malignant prostate tumor tissues showed significantly higher oxidative stress and ROS-induced DNA modifications as compared to normal prostate tissues. Ho and her coworkers (Tam et al., Prostate. 2006 Jan. 1; 66(1):57-69) demonstrated the presence of high oxidative stress induced DNA modifications in the pre-neoplastic lesions occurring in the well studied TRAM P (Transgenic Adenocarcinoma of Mouse Prostate) and Noble rat (Tam et al., Sex Hormones induce direct epithelial and inflammation-mediated oxidative/nitrosative stress that favors prostatic carcinogenesis in the Noble rat. Am. J. Pathol. 2007 October 117(4);1334-41, Epub. 2007 Aug. 23) prostate cancer mouse model of human prostate cancer.
Hence, unregulated mitochondrial ROS production, the resulting oxidative cellular damage-induced-carcinogenesis represent unsolved problems in the art, and present a compelling target for pharmacological drug interventions with pharmaceutical anti-superoxide small molecule drug formulations.
To prevent the cellular damage caused by oxidative stress a number of prior art anti-oxidant therapies have been developed for treating various diseases resulting from oxidative stress. However, most of those inventions are not targeted to other organelles within cells or to the mitochondria and are therefore less than optimally effective.
In recent years, there has been interest in mitochondria-targeting technologies (see Murphy M P. “Selective targeting of bioactive compounds to mitochondria.” Trends Biotechnol. 1997 August; 15(8):326-30). In these approaches, “warhead” groups are covalently coupled via linker groups to a bulky and/or lipophilic cationic moiety such as a quaternary ammonium or phosphonium cationic moiety. These compounds are initially absorbed and accumulate in the cytoplasmic region of cells in response to the negative plasma membrane potential of 30-60 mV (3). Additionally, within a few minutes after drug treatment, the lipophilic cations with a positive 30-60 mV potential permeate through the mitochondrion's lipid layers and selectively accumulate within mitochondria due to the larger mitochondrial membrane potential of 150-170 mV; (negative inside).
Mitochondria-targeted compounds in this class of agents are shown below and include a mitochondria-directed ubiquinone (MitoQ) reported by Murphy and coworkers (U.S. Pat. Nos. 6,331,532 and 7,232,809, and EP Patent 1 047 701 B1, all of which are herein incorporated by reference in their entirety).

MitoQ has shown promise in the treatment of only some, but not all, oxidative stress induced diseases. MitoQ is currently undergoing Phase II clinical trials for the treatment of Parkinson's disease, but it has relatively minor activity against other oxidative stress-induced neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS or Lou Gehrig's Disease). This class of compounds is also disclosed in U.S. Published Application No. U.S. 2008/0032940, herein incorporated by reference in its entirety, in the context of methods for treating cancer.
Other classes of mitochondria-targeted compounds include mitochondria-targeted nitroxides, which have been used in method for treating neurodegenerative disorders (see U.S. Published Application No. 2007/0066572, herein incorporated by reference in its entirety) and mitochondria-targeted antioxidants, which have been used in methods for treating cancer (see U.S. application Ser. No. 11/834,799, entitled “Methods for Reducing Anthracycline-Induced Toxicity,” filed Aug. 7, 2007, herein incorporated by reference in its entirety).
Accordingly, there remains a need for mitochondrially targeted anti-inflammatory, anti-proliferative anti-cancer agents with improved properties and/or toxicity profiles and it is towards the provision of such anti-oxidants, which may be targeted to mitochondria that the various inventions disclosed and described below are directed.